ABSTRACT HIV-1 infection is a major threat in the world and has drawn much attention. The emergence of drug-resistance to most of the HIV-1 inhibitors has led to the crucial call for new inhibitors that can interact with the amino terminal domain of HIV-1 CAPSID (CA) and disrupt viral replication. In this study, molecular dynamics simulation was performed on two class of 4,5-dihydro-1H-pyrrolo[3,4-c]pyrazol-6 one (pyrrolopyrazolone) HIV-1 inhibitors (BI-1 and BI-2) reported to inhibit early postentry stages of viral replication. The effect of N-methylation on the binding of BI-1 and BI-2 to N-terminal HIV-1 capsid of the enzyme was also studied and the structural features such as root mean square deviation (RMSD), root mean square fluctuation (RMSF), the radius of gyration (Rg) were analysed. Density functional theory (DFT) calculations using M06/6311++G(2d,2p) was employed to further investigate the nature of charge transfer of inhibitors based on the second-order perturbation theory. Results obtained showed that N-methylation enhanced the binding of BI-1 with MMPBSA binding energy of −6.2 kcal mol−1 compared to −4.2 kcal mol−1 of BI-1. N-methylation did not have a considerable effect on the binding energy of BI-2, but the MMPBSA binding energy (BI-2_N-methyl) is better, compared to BI-1 and its N-methylated analogue (BI-1_N-methyl). The MMPBSA energies were consistent with the experimental findings.

中文翻译：

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N末端结构域HIV-1衣壳抑制剂结构和动力学的分子动力学和DFT研究

摘要 HIV-1 感染是世界上的主要威胁，并已引起广泛关注。对大多数 HIV-1 抑制剂的耐药性的出现导致迫切需要新的抑制剂，这些抑制剂可以与 HIV-1 CAPSID (CA) 的氨基末端结构域相互作用并破坏病毒复制。本研究对报道的两类4,5-二氢-1H-吡咯并[3,4-c]吡唑-6一（吡咯并吡唑啉酮）HIV-1抑制剂（BI-1和BI-2）进行了分子动力学模拟以抑制病毒复制的早期进入后阶段。还研究了 N-甲基化对 BI-1 和 BI-2 与酶 N 端 HIV-1 衣壳结合的影响，以及均方根偏差 (RMSD)、均方根波动等结构特征。 RMSF），分析回转半径（Rg）。使用 M06/6311++G(2d,2p) 的密度泛函理论 (DFT) 计算被用来进一步研究基于二阶微扰理论的抑制剂电荷转移的性质。获得的结果表明，与 BI-1 的 -4.2 kcal mol-1 相比，N-甲基化增强了 BI-1 的结合，MMPBSA 结合能为 -6.2 kcal mol-1。N-甲基化对 BI-2 的结合能没有显着影响，但与 BI-1 及其 N-甲基化类似物（BI-1_N-甲基）相比，MMPBSA 结合能（BI-2_N-甲基）更好）。MMPBSA 能量与实验结果一致。获得的结果表明，与 BI-1 的 -4.2 kcal mol-1 相比，N-甲基化增强了 BI-1 的结合，MMPBSA 结合能为 -6.2 kcal mol-1。N-甲基化对 BI-2 的结合能没有显着影响，但与 BI-1 及其 N-甲基化类似物（BI-1_N-甲基）相比，MMPBSA 结合能（BI-2_N-甲基）更好）。MMPBSA 能量与实验结果一致。获得的结果表明，与 BI-1 的 -4.2 kcal mol-1 相比，N-甲基化增强了 BI-1 的结合，MMPBSA 结合能为 -6.2 kcal mol-1。N-甲基化对 BI-2 的结合能没有显着影响，但与 BI-1 及其 N-甲基化类似物（BI-1_N-甲基）相比，MMPBSA 结合能（BI-2_N-甲基）更好）。MMPBSA 能量与实验结果一致。